Cortisol response to the Trier Social Stress Test in obese and reduced obese individuals.

Impact of body weight loss, body fat distribution and the nutritional status on the cortisol response to the Trier Social Stress Test (TSST) was investigated in this study. Fifty-one men (17 non-obese, 20 abdominally obese and 14 reduced obese) and 28 women (12 non-obese, 10 peripherally obese and 6 reduced obese) were subjected to the TSST in fed and fasted states. The TSST response was determined using salivary cortisol measurements. The nutritional status (being fed or fasted) had no effect on the cortisol levels during and following the TSST. Reduced obese men exhibited lower cortisol levels than non-obese men. Cortisol levels in obese men were not different from those of non-obese and reduced obese subjects. In women, there was no significant difference between groups. These finding suggest that weight status in men influences cortisol reactivity to a psychological stress and the different responses seen among genders could be linked to the different fat distributions that characterize men and women.

Effects of the CRF1 receptor antagonist SSR125543 on energy balance and food deprivation-induced neuronal activation in obese Zucker rats.

The corticotropin-releasing factor (CRF) system is involved in numerous physiological and behavioral actions, including the regulation of energy balance. We examined the effects of the CRF(1) receptor antagonist, SSR125543, on energy balance and food deprivation-induced neuronal activation in obese rats. Lean (Fa/?) and obese (fa/fa) Zucker rats were treated orally with SSR125543 at a daily dose of 30 mg/kg for 21 days. Rats were killed either fed ad libitum or food deprived for 6 h in order to induce a mild stress response in obese rats. SSR125543 reduced plasma corticosterone levels in lean rats, prevented corticosterone response to fasting in obese rats, and increased CRF mRNA levels in the paraventricular hypothalamic nucleus (PVN) of both lean and obese rats, further confirming that the antagonist partially blocked CRF(1) receptors. SSR125543 increased protein gain in obese rats. Whole carcass analyses showed reduced energy and fat gains in lean rats. Consistent with reduced fat gain, circulating triglyceride and leptin levels were reduced in SSR125543-treated lean rats. In obese rats, circulating glucose levels and the homeostasis model assessment of insulin resistance index of insulin resistance were reduced by SSR125543 treatment. CRF(1) receptor blockade increased uncoupling protein-1 mRNA levels in interscapular brown adipose tissue of obese rats. The antagonist partly blocked the fasting-induced changes in c-fos mRNA levels in the PVN and arcuate nucleus of obese rats. Overall, these results suggest that although SSR125543 had relatively mild effects on energy balance, CRF(1) receptor blockade attenuated several metabolic effects of short-term fasting and improved plasma variables related to the metabolic syndrome and diabetes.

Awakening cortisol response in lean, obese, and reduced obese individuals: effect of gender and fat distribution.

OBJECTIVE: Our goal was to assess the awakening cortisol response (ACR) in obese and reduced obese men and women. RESEARCH METHODS AND PROCEDURES: Fifty-one men (16 lean, 19 abdominally obese, and 16 reduced obese) and 31 women (12 lean, 10 subcutaneously obese, and 9 reduced obese) were selected to participate to this study. Strict ranges of BMI and waist circumference were used to select the participants. Medical examination, psychological assessment, anthropometric measurements, and blood sampling were undergone at the laboratory. Cortisol response to awakening was determined with saliva cortisol sampling being taken immediately at the time of awakening and 30 minutes thereafter over 3 days within a period of 2 months. RESULTS: Men with visceral obesity exhibited an enhanced ACR, whereas this response tends to return to normal in a reduced obese state. In women, peripheral fat accumulation does not modify ACR, but weight loss increased the response. DISCUSSION: These results highlight gender effects on ACR of obese and reduced obese subjects, which could be accounted for by the different fat distribution profiles that characterize men and women. They also provide further support for the usefulness of ACR in assessing the hypothalamic-pituitary-adrenal axis activity status.

Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1.

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.

Involvement of adipose tissues in the early hypolipidemic action of PPARgamma agonism in the rat.

Agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) are insulin sensitizers that potently improve lipemia in rodents. This study aimed to determine the contribution of lipid secretion vs. clearance and the involvement of white adipose tissue (WAT) and brown adipose tissue (BAT) in the rapid hypolipidemic action of PPARgamma agonism. Male rats were treated with rosiglitazone (RSG; 15 mg x kg(-1) x day(-1)) for 1 to 4 days, and determinants of lipid metabolism were assessed postprandially. Serum triglycerides (TG) were lowered (-54%) after 3 days of RSG treatment, due to accelerated clearance from blood without contribution of changes in secretion rates. Both BAT and WAT were the major sites of RSG action on TG clearance, the increase in TG-derived fatty acid (FA) uptake reaching threefold in BAT and 60-90% in WAT depots. Accelerated TG clearance was associated with increased lipoprotein lipase (LPL) activity mostly in BAT. Serum nonesterified FA were lowered (-20%) by a single dose of RSG, an effect associated with increased expression levels of FA binding/transport (fatty acid binding protein-4), esterification (diacylglycerol acyltransferase-1), and recycling glycerol kinase and phosphoenolpyruvate carboxykinase enzymes in BAT and WAT, suggesting FA trapping. After 4 days of RSG treatment, nonesterified fatty acid (NEFA) uptake was also stimulated in both BAT (2.5-fold) and WAT (40%). These findings demonstrate the causal involvement of increased efficiency of LPL-mediated TG clearance and reveal the important contribution of TG-derived and albumin-bound FA uptake by BAT in the rapid hypolipidemic action of PPARgamma agonism in the rat.

Effects of rimonabant (SR141716) on fasting-induced hypothalamic-pituitary-adrenal axis and neuronal activation in lean and obese Zucker rats.

The effects of the cannabinoid-1 receptor (CB(1)) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB(1) antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB(1) antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum-fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB(1) blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB(1) antagonism from exerting beneficial effects on energy and glucose metabolism.

Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism.

In this study, we aimed to establish the mechanisms whereby peroxisome proliferator-activated receptor gamma (PPARgamma) agonism brings about redistribution of fat toward subcutaneous depots and away from visceral fat. In rats treated with the full PPARgamma agonist COOH (30 mg x kg(-1) x day(-1)) for 3 weeks, subcutaneous fat mass was doubled and that of visceral fat was reduced by 30% relative to untreated rats. Uptake of triglyceride-derived nonesterified fatty acids was greatly increased in subcutaneous fat (14-fold) and less so in visceral fat (4-fold), with a concomitant increase, restricted to subcutaneous fat only, in mRNA levels of the uptake-, retention-, and esterification-promoting enzymes lipoprotein lipase, aP2, and diacylglycerol acyltransferase 1. Basal lipolysis and fatty acid recycling were stimulated by COOH in both subcutaneous fat and visceral fat, with no frank quantitative depot specificity. The agonist increased mRNA levels of enzymes of fatty acid oxidation and thermogenesis much more strongly in visceral fat than in subcutaneous fat, concomitantly with a stronger elevation in O2 consumption in the former than in the latter. Mitochondrial biogenesis was stimulated equally in both depots. These findings demonstrate that PPARgamma agonism redistributes fat by stimulating the lipid uptake and esterification potential in subcutaneous fat, which more than compensates for increased O2 consumption; conversely, lipid uptake is minimally altered and energy expenditure is greatly increased in visceral fat, with consequent reduction in fat accumulation.

Hypocholesterolemic action of the selective estrogen receptor modulator acolbifene in intact and ovariectomized rats with diet-induced hypercholesterolemia.

Acolbifene (ACOL) is a fourth-generation selective estrogen receptor modulator (SERM) that has strong and pure antiestrogenic properties toward estrogen-sensitive cancers, but improves energy and lipid metabolism in an estrogen-like fashion in rodent models. The aim of this study was to determine the potency of ACOL to reduce cholesterolemia in a dietary model of hypercholesterolemia and to establish its mechanisms of action. Intact and ovariectomized (OVX) female rats were treated for 3 weeks with ACOL, and serum cholesterol and liver determinants of cholesterol metabolism were assessed. Acolbifene prevented both diet- and ovariectomy-induced weight gain and completely prevented diet-induced hypercholesterolemia. Relative to a reference chow diet, the high-cholesterol diet decreased the high-density lipoprotein (HDL) cholesterol fraction, which remained unaffected by ACOL, indicating that in hypercholesterolemic conditions, ACOL modulated only the non-HDL fraction. No impact of ACOL on determinants of liver cholesterol synthesis was observed. In contrast, ACOL increased hepatic low-density lipoprotein receptor protein in both intact and OVX rats, which was negatively correlated with serum total and non-HDL cholesterol (r=-0.59, P<.0001), suggesting a contribution of receptor-mediated hepatic uptake of cholesterol-rich lipoproteins to the hypocholesterolemic effect of ACOL. These findings establish that ACOL retains its powerful cholesterol-lowering action in diet-induced hypercholesterolemia and suggest that the SERM acts in such conditions through favoring hepatic low-density lipoprotein receptor-mediated uptake of cholesterol transported by non-HDL lipoprotein fractions.

The selective estrogen receptor modulator acolbifene reduces cholesterolemia independently of its anorectic action in control and cholesterol-fed rats.

The cancer-preventing selective estrogen receptor modulator (SERM) acolbifene (ACOL) exerts a potent and pure antiestrogenic action in the mammary gland and uterus, yet it displays beneficial, estrogen-like actions on energy and lipid metabolism in rodents. The compound reduces food intake and strongly decreases cholesterolemia in rats fed a cholesterol-free diet. This study was designed to establish whether the anorectic effect of ACOL is involved in its cholesterol-lowering action, and whether the compound retains its ability to lower cholesterol concentrations in rats with diet-induced hypercholesterolemia. Female rats were fed a purified diet devoid of cholesterol (reference diet) or containing 2% cholesterol (C-diet); they were either not treated or treated daily with ACOL or not treated and pair-fed to the ACOL-treated rats. The C-diet did not affect food intake or weight and fat gains. ACOL reduced food intake (16%) and weight gain (45%, mainly fat) similarly in both dietary cohorts. ACOL, but not pair feeding, reduced cholesterolemia by 33% in rats fed the reference diet. As expected, the C-diet raised serum total cholesterol almost 3-fold and this increase was largely prevented by ACOL but not by pair feeding. Cholesterol was reduced by ACOL, mainly in the HDL fraction, in rats fed the reference diet, but only in the non-HDL fraction in those fed the C-diet. In livers of rats fed the reference diet, ACOL, but not pair feeding, increased protein abundance of the scavenger receptor, class B, type 1, and the LDL receptor, thought to be involved in ACOL-mediated cholesterol lowering. These findings demonstrate that the potent hypocholesterolemic action of ACOL is independent of the concomitant reduction in food intake and fat accretion, and that such action occurs in rats with overt diet-induced hypercholesterolemia.

Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors.

This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r = 0.80, P < 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection.

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists improve insulin sensitivity and lipemia partly through enhancing adipose tissue proliferation and capacity for lipid retention. The agonists also reduce local adipose glucocorticoid production, which may in turn contribute to their metabolic actions. This study assessed the effects of a PPARgamma agonist in the absence of glucocorticoids (adrenalectomy, ADX). Intact, ADX, and intact pair-fed (PF) rats were treated with the PPARgamma agonist rosiglitazone (RSG) for 2 wk. RSG increased inguinal (subcutaneous) white (50%) and brown adipose tissue (6-fold) weight but not that of retroperitoneal (visceral) white adipose tissue. ADX but not PF reduced fat accretion in both inguinal and retroperitoneal adipose depots but did not affect brown adipose mass. RSG no longer increased inguinal weight in ADX and PF rats but increased brown adipose mass, albeit less so than in intact rats. RSG increased cell proliferation in white (3-fold) and brown adipose tissue (6-fold), as assessed microscopically and by total DNA, an effect that was attenuated but not abrogated by ADX. RSG reduced the expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in all adipose depots. RSG improved insulin sensitivity (reduction in fasting insulin and homeostasis model assessment of insulin resistance, both -50%) and triacylglycerolemia (-75%) regardless of the glucocorticoid status, these effects being fully additive to those of ADX and PF. In conclusion, RSG partially retained its ability to induce white and brown adipose cell proliferation and brown adipose fat accretion and further improved insulin sensitivity and lipemia in ADX rats, such effects being therefore independent from the PPARgamma-mediated modulation of glucocorticoids.

Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.

Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice.

The objective of the present study was to investigate the effects of the antiepileptic drug topiramate (TPM) on components of energy balance in lean and obese (ob/ob) mice in the presence or absence of leptin. Lean and ob/ob mice infused with either leptin or phosphate-buffered saline were treated with TPM for 7 days. TPM was mixed into the diet and administered at a dose of 60 mg/kg/day, whereas leptin was infused at the rate of 100 microg/kg/day using osmotic minipumps, which were subcutaneously implanted in the interscapular region. Food intake and body weight were monitored throughout the study. Body composition was measured prior to and following treatment with TPM and leptin, using dual-energy X-ray absorptiometry (DEXA). Glucose (glucose oxidase method) and insulin (radioimmunoassay) were also determined. TPM and leptin significantly reduced body weight gain, food intake and body fat gain in obese mice. The effects of TPM and leptin on fat gain were also statistically significant in lean animals. There was no interaction of TPM and leptin on the energy balance variables, the effects of the two substances being additive instead. Leptin abrogated hyperinsulinemia in obese mutants whereas TPM did not alter insulin levels in either lean or obese mice. The combination of leptin and TPM led to the normalization of glucose levels in obese mice. Our study demonstrates an effect of TPM in leptin-deficient animals, which suggests that TPM does not require the presence of leptin to exert its effect. They also show that the effects of leptin and TPM can be additive. The treatment with leptin in ob/ob mice neither accentuated nor blunted the effect of TPM on energy balance.

Comparative effects of the antipsychotics sulpiride or risperidone in rats. I: bodyweight, food intake, body composition, hormones and glucose tolerance.

Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.

Resistance of adipose tissue lipoprotein lipase to insulin action in rats fed an obesity-promoting diet.

This study aimed to assess whether adipose lipoprotein lipase (LPL) becomes resistant to insulin in a nutritional model of resistance of glucose metabolism to insulin. Sprague-Dawley rats were fed for 4 wk chow or a purified high-sucrose, high-fat (HSHF) diet that induced overt insulin resistance. Rats were fasted for 24 h and then refed chow for 1, 3, or 6 h. The postprandial rise in insulinemia was similar in both dietary cohorts, whereas glycemia was higher in HSHF-fed than in chow-fed animals, indicating glucose intolerance and insulin resistance. In chow-fed rats, adipose LPL activity increased two- to fourfold postprandially, but only minimally (30%) in HSHF-fed rats. Muscle LPL decreased postprandially in HSHF-fed rats, suggesting intact sensitivity to insulin, but it increased in chow-fed animals. Peak postprandial triglyceridemia was higher (+70%) in insulin-resistant than in control rats. The postprandial rate of appearance of triglycerides in the circulation was similar in control and insulin-resistant rats, indicating that hypertriglyceridemia of the latter was the result of impaired clearance. These results demonstrate that adipose LPL becomes resistant to insulin in diet-induced IR and further suggest that, under certain nutritional conditions, modifications in adipose LPL modulation associated with insulin resistance, along with low muscle LPL, heightens postprandial hypertriglyceridemia through attenuated triglyceride clearance.